Many pathophysiological mechanisms that underlie weight disorders can be managed through modulation of central regulatory elements in energy homeostasis, including food intake and energy expenditure. Dietary supplements that contain pregnane glycoside-enriched extract from a desert milkweed plant Hoodia are among the most popular botanical weight-loss remedies despite the lack of pre-clinical, clinical, and toxicological research evidence. To validate the physiological and pharmacological effects of pregnane glycoside-enriched botanicals, we screened plants that belong to milkweed family and identified swamp milkweed, Asclepias incarnata, a common and fast growing North American relative of Hoodia, as an alternative source of active ingredients. A. incarnata extract produced an acute reduction in food intake that reduced fat deposition and improved markers of insulin sensitivity, possibly through a mechanism requiring gut-brain communication via primary vagal afferents. Studies involving chronic treatment with the extract and pair feeding to control for its effect on food intake supported an additional metabolic role ofthe extract independent of its effects on food intake. Based on these observations, we hypothesize that incarnatin impacts energy homeostasis by promoting satiety and stimulating energy expenditure. Thus our primary goal is to understand the complementary components ofthe mechanism(s) by which this botanical enhances satiety and attenuates the progression to metabolic syndrome through three specific aims: 1) To identify the site of action and mechanism(s) through which incarnatin controls food intake;2) To determine the mechanisms of energy expenditure in the antiobesity activity of incarnatin;3) To define bioavailability of incarnatin and its bioactive component(s) using a functional model ofthe human digestive system under controlled conditions and evaluate their structure-activity properties using cell culture assays.